Synthesis of classical and a nonclassical 2-amino-4-oxo-6-methyl-5- substituted pyrrolo[2,3-d]pyrimidine antifolate inhibitors of thymidylate synthase

Aleem Gangjee, Farahnaz Mavandadi, Roy L. Kisliuk, Sherry Queener

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Compounds 2-5 were designed as potential antifolate nonpolyglutamatable inhibitors of thymidylate synthase (TS). These analogues are structurally related to 2-amino-4-oxo-5-substituted quinazolines and 2-amino-4-oxo-5- substituted pyrrolo[2,3-d]pyrimidines which have shown excellent inhibition of TS and, for the quinazoline, significant promise as clinically useful antitumor agents. Compounds 2-4 were synthesized by appropriate amine exchange reactions on pivaloyl-protected 5-dimethylaminomethyl-substituted 6- methyl pyrrolo[2,3-d]pyrimidine 7 which in turn was obtained from the Mannich reaction of pivaloylated-6-methyl pyrrolo[2,3-d]pyrimidine 6. In instances where the amine exchange reaction was sluggish, the Mannich base was quaternized with methyl iodide which afforded much faster exchange reaction with improved yields. For compound 5, 4-mercaptopyridine was used as the nucleophile and reacted with 7. The analogues 2-4 inhibited Lactobacillus casei (lc) TS and recombinant human (h) TS with IC50 in the 10-4 to 10- 5 M range. Compound 5 inhibited lcTS and hTS 20% at 26 and 25 μM, respectively. In addition, compound 5 inhibited the growth of Pneumocystis carinii and Toxoplasma gondii cells in culture by 76% at 32 x 10-6 M and 50% at 831 x 10-6 M, respectively.

Original languageEnglish
Pages (from-to)2272-2279
Number of pages8
JournalJournal of Medicinal Chemistry
Volume42
Issue number12
DOIs
StatePublished - Jun 17 1999

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Folic Acid Antagonists
Thymidylate Synthase
Quinazolines
Amines
Mannich Bases
Lactobacillus casei
Pneumocystis carinii
Nucleophiles
Toxoplasma
Antineoplastic Agents
Inhibitory Concentration 50
Cell Culture Techniques
Pyrrolo(2,3-d)pyrimidine
Growth

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Synthesis of classical and a nonclassical 2-amino-4-oxo-6-methyl-5- substituted pyrrolo[2,3-d]pyrimidine antifolate inhibitors of thymidylate synthase. / Gangjee, Aleem; Mavandadi, Farahnaz; Kisliuk, Roy L.; Queener, Sherry.

In: Journal of Medicinal Chemistry, Vol. 42, No. 12, 17.06.1999, p. 2272-2279.

Research output: Contribution to journalArticle

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abstract = "Compounds 2-5 were designed as potential antifolate nonpolyglutamatable inhibitors of thymidylate synthase (TS). These analogues are structurally related to 2-amino-4-oxo-5-substituted quinazolines and 2-amino-4-oxo-5- substituted pyrrolo[2,3-d]pyrimidines which have shown excellent inhibition of TS and, for the quinazoline, significant promise as clinically useful antitumor agents. Compounds 2-4 were synthesized by appropriate amine exchange reactions on pivaloyl-protected 5-dimethylaminomethyl-substituted 6- methyl pyrrolo[2,3-d]pyrimidine 7 which in turn was obtained from the Mannich reaction of pivaloylated-6-methyl pyrrolo[2,3-d]pyrimidine 6. In instances where the amine exchange reaction was sluggish, the Mannich base was quaternized with methyl iodide which afforded much faster exchange reaction with improved yields. For compound 5, 4-mercaptopyridine was used as the nucleophile and reacted with 7. The analogues 2-4 inhibited Lactobacillus casei (lc) TS and recombinant human (h) TS with IC50 in the 10-4 to 10- 5 M range. Compound 5 inhibited lcTS and hTS 20{\%} at 26 and 25 μM, respectively. In addition, compound 5 inhibited the growth of Pneumocystis carinii and Toxoplasma gondii cells in culture by 76{\%} at 32 x 10-6 M and 50{\%} at 831 x 10-6 M, respectively.",
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